Extranodal natural killer/T-cell lymphoma, nasal type

What every physician needs to know:

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is an aggressive non-Hodgkin lymphoma (NHL) which represents a rare specific extranodal subtype of peripheral T-cell lymphoma (PTCL). ENKL is most commonly seen in Pacific Rim countries and most studies are from the Far East. It has been estimated that ENKL represents 10% of all PTCL globally, comprising over 20% of cases in Japan, and about 5% in North America.

The malignant lymphocytes in ENKL almost always harbor Epstein-Barr virus (EBV) and latent membrane proteins are commonly expressed. Similar to other subtypes of NHL, including endemic Burkitt lymphoma, post transplant lymphoproliferative disorders, and cases of Hodgkin lymphoma and diffuse large B-cell lymphoma EBV is believed to be the driver of malignant transformation in ENKL.

The most common site of presentation of ENKL is the nasopharynx; however extra-nasal, extra-nodal (skin, intestine, central nervous system [CNS]) presentations do occur. The staging of NHL follows the Ann Arbor staging system. However, the Ann Arbor system has recognized shortcomings for primary extranodal lymphomas, so other schema defining localized and extensive disease have been proposed. In ENKL, no alternate staging criteria had gained uniform acceptance and using a modified interpretation of the Ann Arbor staging to distinguish localized (stage IE, IIE) and advanced (IIIE, IV) stages is common.

Regardless of the system used, there is a discrete difference in the treatment and prognosis between localized and advanced disease.

ENKL is an aggressive lymphoma with survival in an untreated patient measured in weeks to months. In the retrospective International Peripheral T-cell Lymphoma Project, the median overall survival among patients with ENKL was 3 years for localized and 8 months for advanced disease. Despite the short median overall survival, with most current treatment approaches, a significant number of patients are cured. However, most of the long term survivors come from those with localized disease at presentation. While there is no single standard of care for the treatment of ENKL, radiation and/or chemotherapy are used for all patients able to undergo therapy, with incorporation of high dose therapy and stem cell transplantation becoming a more common approach in advanced stages.

Are you sure your patient has extranodal natural killer/T-cell lymphoma, nasal type? What should you expect to find?

- This disease commonly presents in the skin and expresses CD56, but is no longer thought to be of NK or T-cell derivation.

Wegener's granuloma

Which individuals are most at risk for developing extranodal natural killer/T-cell lymphoma, nasal type:

Asian heritage. Higher frequency is also seen in individuals from other Pacific Rim countries including South America.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies required:

Adequate biopsy

- Adequate biopsy, reviewed by an expert hematopathologist, is the only way to reliably make the diagnosis. Beware of very small biopsies or fine needle aspirates, as EBV may be seen in a variety of malignant and reactive processes.

Complete blood count

- Elevated while blood cell count given inflammatory nature of lesion and concern for secondary infection.

Comprehensive metabolic panel (CMP)

- In advanced disease, may present with metabolic derangements consistent with aggressive lymphoma.

Lactate dehydrogenase

- Often elevated, given the aggressive nature of the underlying disease.

Ferritin

- Often elevated (greater than 1,000) in those with, or progressing towards, hemophagocytic syndrome.

Quantitiative EBV polymerase chain reaction (serum)

- May be predictive of disease extent, as well as a measure of treatment response, and possibly a predictor of relapse

What imaging studies (if any) will be helpful in making or excluding the diagnosis of extranodal natural killer/T-cell lymphoma, nasal type?

Helpful imaging studies:

Positron emission tomography/computed tomography (PET/CT)scan

- Evaluate for disease outside of localized field (upstage to advanced disease). CT is standard, although we have found PET to be particularly useful in identifying and following extranodal disease.

- Even with the above studies, direct visualization by ear, nose and throat (ENT) exam and biopsies, is often helpful in defining the true extent of disease or excluding residual inflammation post treatment when imaging is equivocal.

If you decide the patient has extranodal natural killer/T-cell lymphoma, nasal type, what therapies should you initiate immediately?

Best therapies often require planning and consultation with hematology/oncology in addition to radiation oncology input. Therefore, careful evaluation of extent of disease and expert planning of treatment, should be completed as quickly as possible.

More definitive therapies?

Historically, ENKL was thought to be somewhat chemo-insensitive, or less chemo sensitive than other aggressive lymphomas, and radiation therapy alone with doses significantly higher than typically used for lymphoma involved areas was preferred for localized disease.

Most of the data showing a lack of benefit with the addition of chemotherapy to radiation therapy was with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based regimen. Newer, more active chemotherapy regimens are now changing this paradigm. Currently, no universally accepted approach exists in the treatment of ENKL, and higher dose radiation therapy alone is still considered in truly localized disease. However, as discussed below, many, if not most patients with early stage (localized) disease, are now receiving either sequential or concurrent combined modality approaches. Patients who present in advanced stages typically receive combination chemotherapy and often high dose therapy approaches, with adjuvant radiation to bulky or high risk sites.

CHOP chemotherapy in a sequential regimen for localized disease yielded low complete response (CR) rate of 35% after four cycles. The non-antracycline based regimen of ifosphamide, methotrexate, etoposide, and prednisone (IMEP) resulted in a CR rate of 79% alone in localized disease, but had poor durability, with a 64% relapse rate locally, leading to dependence on high intensity radiotherapy to achieve disease control. An encouraging alternative regimen has been the concurrent regimen DeVIC (dexamethasone, etoposide, ifosphamide, and carboplatin) with 50cGy of radiation for IE presentation and 50.4cGy for IIE disease, which resulted in a CR rate of 77%.

In primary refractory localized disease, relapsed, and advanced disease, L-asparginase has emerged as a very active agent in combination with other cytotoxic agents. Asparaginase containing regimens are now our first choice for initial therapy in ENKL. The regimens of AspaMetDEx (L-asparaginase, methotrexate, and dexamethasone) and SMILE (steroid [dexamethasone], methotrexate, L-asparaginase, ifosphamide, and etoposide) have both shown high response rates in the relapse setting, and SMILE has also been used as initial therapy. For those unfamiliar with these regimens, both regimens have significant hematologic toxicity and L-asparaginase adverse effects include hypersensitivity reactions, pancreatitis, and hepatic toxicities.

The role of consolidation with high dose therapy and autologous or allogeneic stem cell transplantation, remains an attractive strategy employed frequently in the relapsed/refractory setting, or as consolidation for patients with advanced disease. Pilot studies are ongoing, using a strategy of a short course of an asparaginase containing regimen, followed by radiation therapy for those with localized disease. For those with disease that extends outside of an acceptable radiation field, additional cycle or cycles of the same chemotherapy regimen, often followed by radiation therapy to bulk or high risk sites, and strong consideration of consolidation, with either autologous or allogeneic stem cell transplantation use, if disease is being studied.

What other therapies are helpful for reducing complications?

What should you tell the patient and the family about prognosis?

The diagnosis of ENKL is often early with at least two thirds of patients presenting with localized disease. Given the rarity of the disease, no standard treatment has been established. The most extensive review of disease specific prognosis was performed by the International Peripheral T-cell Lymphoma Project in localized and advanced ENKL; the median overall survival was between 3 and 4 years. However, some patients are cured of this disease and newer more active therapies appear to be markedly changing the outcome for many.

"What if" scenarios.

Extranasal extranodal presentations

Occurs in approximately 10% of cases of ENKL. There is some suggestion that these may be more aggressive than the nasal subtype and localized presentation may be considered for maintenance or consolidative strategies.

EBV polymerase chain reaction positivity post treatment

Serum EBV quantitative values appear to be a surrogate for extent of disease, and having undetectable levels at the end of treatment predicts for a lower rate of relapse. While detectable levels post therapy or rising levels in follow-up, often precede recurrence, there is currently no data to show that further treatment in EBV positive patients improves outcomes.

Pathophysiology

ENKL almost always harbors EBV within the tumor cell and EBC is believed to drive lymphomagenesis.

What other clinical manifestations may help me to diagnose extranodal natural killer/T-cell lymphoma, nasal type?

Other manifestations:

Adequate biopsy, reviewed by an expert hematopathologist is the only way to reliably make the diagnosis